This invention relates to novel oligopeptides either derived from a corn protein or synthesized, an angiotensin converting enzyme inhibitor containing as an effective ingredient at least one of the oligopeptides, a hypotensive agent containing as an effective ingredient at least one of the oligopeptides, a method for inhibition of the angiotensin converting enzyme using at least one of certain oligopeptides, and a method for treatment or prophylaxis of hypertension using at least one of certain oligopeptides.
It is well known that the renin-angiotensin system has profound relation to crisis of hypertension, and in this renin-angiotensin system the angiotensin converting enzyme (EC 3.4.15.1, hereinafter sometimes referred to as ACE) plays an important role. Namely, ACE acts on angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) formed by decomposition of angiotensin, which was secreted in the liver, by an enzyme renin produced in the kidney, and converts it to angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). This angiotensin II has activities, for example, to heighten the blood pressure by contracting the smooth muscles of the blood vessel walls and further promote secretion of aldosterone by action on the adrenal cortex. Separately, an enzyme kallikrein, which exists in the plasma, decomposes a protein called kininogen to produce bradykinin which dilates the blood vessel and lowers the blood pressure, but this bradykinin is decomposed and inactivated by action of ACE. Thus, ACE forms, on the one hand, a blood pressure heightening peptide (angiotensin II), and decomposes, on the other hand, a blood pressure lowering peptide (bradykinin), and as a result heighten the blood pressure. Therefore, it is possible to prevent increase of the blood pressure (lowering of the blood pressure) by inhibition of activities of this enzyme.
Heretofore, there have been known many ACE activity inhibiting substances, for example, several peptidic inhibitors, as the starter, obtained from snake venoms, and synthetic substances such as captopril (D-2-methyl-3-mercaptopropanoyl-L-proline). Among them captopril is already practically used as an oral hypotensive agent.
Further, recently, ACE inhibiting substances were found also in microorganisms and various foods and are being investigated for putting them to practical use as a hypotensive agent (Kunio Suetsuna, "Hakko to Kogyo" (Fermentation and Industry) 46 (No. 3), 179-182 (1988)). Further, a report on ACE inhibiting substances derived from food proteins, particularly, casein and corn seed proteins was made in Susumu Maruyama, Biosciences and Industry 47 (No. 11), 38-42 (1989). Further, reports were also made on ACE inhibiting substances derived from corn seed proteins in Susumu Maruyama et al., Lecture Gists for the 1988 Year Great Annual Meeting of Nippon Hakko Kogaku Kai (Japan Fermentation Engineering Society), p. 23 (1988); Susumu Maruyama et al., Lecture Gists for the 1989 Year Meeting of Nippon Nogei Kagaku Kai (Japan Society for Bioscience, Biotechnology and Agrochemistry), p. 8 (1989); Shinsuke Miyoshi et al., Gists for the 1989 Year Meeting of Nippon Eiyo Shokuryo Gakki (Japan Nutrition and Food Society) p. 113 (1989); and Shinsuke Miyoshi et al., Nippon Nogei Kagaku Kaishi (Journal of Japan Agricultural Chemistry Society), 64(3), 555, 1990 (Lecture Gists for the 1990 Year Great Annual Meeting).